Solubilizing hydrophobic and amphiphilic active drug substances for efficient oral delivery remains a problem. At the minimum, an efficient drug delivery system should function to deliver a therapeutically effective dosage of any given compound to achieve the desired therapeutic concentration. Maximum strength formulations provide higher doses of active drug substances and therapeutic efficacy while minimizing the number of doses required. These formulations can increase patient satisfaction and compliance; however, they can be challenging to formulate for poorly soluble active drug substances often because of precipitation of the active, and often these drugs are formulated as tablets or as a suspension.
Soft capsules have gained popularity and acceptance over tablets and hard capsules due to their elegant and clear appearance. Soft capsules are in general easier to swallow, are hermetically sealed, and can easily be colored to protect ingredients from light. Additionally, soft capsules often allow for increased absorption and bioavailability by the large range of methods for preparing active drug ingredients and matrix fills.
Current methodologies for increasing the solubility of poorly soluble active drug substances for use in soft capsules include the development of emulsion type matrices of either oil in hydrophilic (o/p) or hydrophilic in oil (p/o). These can include both microemulsions (about 10-200 nm) and macroemulsions (>1000 nm). Such emulsions are typically generated by the solubilization of the active ingredient in an oil phase, which is then dispersed in an aqueous environment with a surfactant. These formulations can often become visibly cloudy or discolored to the naked eye. Furthermore, typically used emulsions can be thermodynamically unstable leading to phase separation and reduced bio absorption. Even microemulsion systems, such as self-microemulsifying drug delivery systems (SMEDDS), which are inherently more stable than standard emulsions can become unstable depending on changes in temperature and pH. Moreover, microemulsions require large amounts of surfactant to stabilize the microemulsion, which may exceed safe levels for ingestion.
In addition, many hydrophobic and amphiphilic drugs are exported by the P-glycoprotein (P-gp) efflux active transporter leading to decreased in vivo permeability. For example, this process of active efflux leads to multi-drug resistance mechanisms in cancer and decreased absorption and bioavailability of many anti-cancer drugs. In addition, many other hydrophobic and amphiphilic drugs are highly susceptible to P-gp mediated efflux due to interactions with the cellular bilayer lipid membrane. In particular, substrates of the P-gp transporter are most commonly amphiphilic, and thus, have spatially separate hydrophilic and hydrophobic moieties. One approach described in US Patent Application Publication No. US 20070142266 is to couple a drug that is a P-gp substrate with a P-gp inhibitor to minimize P-gp-mediated export. While there are numerous direct and indirect P-gp inhibitors available, each of these inhibitors can have unintended side effects and may not be compatible with all active drug ingredients. Other approaches are in modifying the salt form of the active drug ingredient to lower the affinity between the P-gp efflux transporter and drug. Another approach described in U.S. Pat. No. 7,910,553 includes generating prodrug forms of an active ingredient with P-gp protective amino acid sequences. These approaches, however, can decrease the bio absorption of a drug and change its pharmacokinetics. Thus, the ideal P-gp inhibitor should have no pharmacological activity and be non-toxic.
Accordingly, there is an unmet need in the field for soft capsule pharmaceutical formulations that are suitable for poorly soluble active drug substances, which increase bioavailability and inhibit or reduce the affinity of the P-gp transporter for poorly soluble active drug substances.